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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2019

Open Access 01-12-2019 | Acute Myeloid Leukemia | Research

Nuclear factor of activated T-cells, NFATC1, governs FLT3ITD-driven hematopoietic stem cell transformation and a poor prognosis in AML

Authors: Maria Solovey, Ying Wang, Christian Michel, Klaus H. Metzeler, Tobias Herold, Joachim R. Göthert, Volker Ellenrieder, Elisabeth Hessmann, Stefan Gattenlöhner, Andreas Neubauer, Dinko Pavlinic, Vladimir Benes, Oliver Rupp, Andreas Burchert

Published in: Journal of Hematology & Oncology | Issue 1/2019

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Abstract

Background

Acute myeloid leukemia (AML) patients with a high allelic burden of an internal tandem duplication (ITD)-mutated FMS-like Tyrosine Kinase-3 (FLT3) have a dismal outcome. FLT3ITD triggers the proliferation of the quiescent hematopoietic stem cell (HSC) pool but fails to directly transform HSCs. While the inflammatory transcription factor nuclear factor of activated T-cells 2 (NFAT2, NFATC1) is overexpressed in AML, it is unknown whether it plays a role in FLT3ITD-induced HSC transformation.

Methods

We generated a triple transgenic mouse model, in which tamoxifen-inducible Cre-recombinase targets expression of a constitutively nuclear transcription factor NFATC1 to FLT3ITD positive HSC. Emerging genotypes were phenotypically, biochemically, and also transcriptionally characterized using RNA sequencing. We also retrospectively analyzed the overall survival of AML patients with different NFATC1 expression status.

Results

We find that NFATC1 governs FLT3ITD-driven precursor cell expansion and transformation, causing a fully penetrant lethal AML. FLT3ITD/NFATC1-AML is re-transplantable in secondary recipients and shows primary resistance to the FLT3ITD-kinase inhibitor quizartinib. Mechanistically, NFATC1 rewires FLT3ITD-dependent signaling output in HSC, involving augmented K-RAS signaling and a selective de novo recruitment of key HSC-transforming signaling pathways such as the Hedgehog- and WNT/B-Catenin signaling pathways. In human AML, NFATC1 overexpression is associated with poor overall survival.

Conclusions

NFATC1 expression causes FLT3ITD-induced transcriptome changes, which are associated with HSC transformation, quizartinib resistance, and a poor prognosis in AML.
Appendix
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Metadata
Title
Nuclear factor of activated T-cells, NFATC1, governs FLT3ITD-driven hematopoietic stem cell transformation and a poor prognosis in AML
Authors
Maria Solovey
Ying Wang
Christian Michel
Klaus H. Metzeler
Tobias Herold
Joachim R. Göthert
Volker Ellenrieder
Elisabeth Hessmann
Stefan Gattenlöhner
Andreas Neubauer
Dinko Pavlinic
Vladimir Benes
Oliver Rupp
Andreas Burchert
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-019-0765-y

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